TW202415661A - Crystalline forms of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan -2-yl)-1h,2h,3h,4h,5h-[1,4]diazepino[1,7-a]indol-9-yl]-1,2- dihydropyridin-2-one and salts thereof, method of preparation, and uses thereof - Google Patents
Crystalline forms of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan -2-yl)-1h,2h,3h,4h,5h-[1,4]diazepino[1,7-a]indol-9-yl]-1,2- dihydropyridin-2-one and salts thereof, method of preparation, and uses thereof Download PDFInfo
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- TW202415661A TW202415661A TW112121810A TW112121810A TW202415661A TW 202415661 A TW202415661 A TW 202415661A TW 112121810 A TW112121810 A TW 112121810A TW 112121810 A TW112121810 A TW 112121810A TW 202415661 A TW202415661 A TW 202415661A
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- dihydropyridin
- chloropyridin
- indol
- propan
- methoxy
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Abstract
Description
本揭露內容係關於4-[(5-氯吡啶-2-基)甲氧基]-1-[3-(丙-2-基)-1H,2H,3H,4H,5H-[1,4]二氮呯并[1,7-a]吲哚-9-基]-1,2-二氫吡啶-2-酮(化合物1)之鹽酸鹽,其為可用於治療及/或預防肥胖症、肥胖症相關之共病病況及併發症、糖尿病、代謝失調、冠狀動脈疾病、腦血管疾病、周邊動脈疾病、高血壓、內分泌失調、精神疾患、人格障礙、飲食障礙、睡-醒周期障礙、物質濫用及成癮障礙、慢性肝臟及腎臟疾病、腸胃道疾病、肌肉骨骼系統之慢性病況、骨質疏鬆症、癌症、以及普威二氏症候群(PWS)或PWS之一或多種症狀的強效口服活性選擇性黑色素集中荷爾蒙受體1(MCHR1)拮抗劑。本揭露內容亦關於呈游離鹼形式之4-[(5-氯吡啶-2-基)甲氧基]-1-[3-(丙-2-基)-1H,2H,3H,4H,5H-[1,4]二氮呯并[1,7-a]吲哚-9-基]-1,2-二氫吡啶-2-酮的晶形、其鹽酸鹽之不同晶形、製造彼之方法、其醫藥組成物、以及其治療應用。The present disclosure relates to the hydrochloride of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one (Compound 1), which is useful for treating and/or preventing obesity, obesity-related comorbidities and complications, diabetes, metabolic disorders, coronary artery disease, A potent, orally active, selective melanin concentrating hormone receptor 1 (MCHR1) antagonist for cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, mental illness, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic conditions of the musculoskeletal system, osteoporosis, cancer, and Prader-Willi syndrome (PWS) or one or more symptoms of PWS. The present disclosure also relates to crystalline forms of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one in free base form, different crystalline forms of its hydrochloride salt, methods for making the same, pharmaceutical compositions thereof, and therapeutic applications thereof.
MCHR1拮抗劑,包含呈游離鹼形式之4-[(5-氯吡啶-2-基)甲氧基]-1-[3-(丙-2-基)-1H,2H,3H,4H,5H-[1,4]二氮呯并[1,7-a]吲哚-9-基]-1,2-二氫吡啶-2-酮(如下描述,於下文中稱為化合物1)、及其順丁烯二酸鹽係於WO 2016/166684 A1中提出。 MCHR1 antagonists, including 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diaza[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one (described below, hereinafter referred to as Compound 1) in free base form, and maleic acid salts thereof are proposed in WO 2016/166684 A1.
黑色素集中荷爾蒙(MCH)於能量恆定中扮演多元的角色,以及為下視丘食物攝取量及能量消耗之控制的中心(Pissios等人,
Endocr Rev2006, 27(6):606-620)。MCH已因其對於食物攝取量及體重之影響而備受矚目,以及其受體MCHR1仍為肥胖症治療的可行目標之一(Pissios P.,
Peptides2009, 30(11):2040-2044)。MCH為進食之最強效中樞刺激劑之一,調節能量平衡及情緒(Pissios等人,
Endocrinology2003, 144(8):3514-3523;Pissios等人,
Endocr Rev2006, 27(6):606-620;Forray C.,
Curr Opin Pharmacol2003, 3: 85-89;Qu等人,
Nature1996, 380: 243-47;Hervieu G.,
Expert Opin Ther Targets2003, 7: 495-511;Chung等人,
J Mol Neurosci2011, 43:115-21)。普威二氏症候群(PWS)為罕見的複雜性神經發展遺傳疾病,係由不存在染色體15q11.2-q13之父系衍生區中之印記基因表現所造成。PWS為危及生命的肥胖症之最常見的綜合症病因,其評估發病率為1/10 000至1/25 000活產數,於男性及女性二者中同等地發生,且係跨種族的。嚴重的過食症所造成之綜合症狀肥胖症源自父系複製缺失案例中總是涉及的小核仁C/D box RNA 116(SNORD116)叢集缺失(因證實其為最小缺失區)之神經發展結果(Holm等人,
Pediatrics1993, 91:398-402;Gunay-Aygun等人,
Pediatrics2001, 108:E95;Duker等人,
Eur. J. Hum. Genet.2010;18: 1196-201;de Smith等人,
Hum. Mol. Genet.2009, 18:3257-65;Bieth等人,
Eur. J. Human Genet.2015, 23:252-255;Polex-Wolf等人,
J. Clin. Invest. 2018, 128:960-969;Tan等人,Genes 2020, 11:128;Chung等人,
Open Biology2020, 10:200195)。為PWS中之關鍵行為症狀的過食症對於病患及照顧者福祉之顯著影響遠超出單純的體重增加作用。過食症之管理在照顧者當中被列為PWS治療目標之優先順序當中最高優先等級。PWS之無法控制的食慾、體重增加及生殖能力受損可由因為外側下視丘中之ORX數量減少導致「制衡」喪失而造成過度活躍MCH神經元來解釋。防止MCH過度活躍最可能改善MCH-ORX平衡,其最終可幫助病患減少進食相關之症狀。根據最新的臨床前報告,MCH-MCHR1系統係因ORX控制受損而過度活躍,PWS病患可從MCHR1拮抗劑治療獲益而得到對於過食症及肥胖症之控制(Pace M.,
JCI Insight2020, 5:e137495;Pace等人,
Hum. Mol. Genet.2020, 29:2051-2064;Linehan等人,
Mol. Meatabolism2020, 36:100977;Linehan等人,
J. Physiol2022, 596:305-316)。因此,MCHR1拮抗劑可用於治療與黑色素集中荷爾蒙受體1活性相關之疾病或病況,諸如肥胖症、肥胖症相關之共病病況及併發症、糖尿病、代謝失調、冠狀動脈疾病、腦血管疾病、周邊動脈疾病、高血壓、內分泌失調、精神疾患、人格障礙、飲食障礙、睡-醒周期障礙、物質濫用及成癮障礙、慢性肝臟及腎臟疾病、腸胃道疾病、肌肉骨骼系統之慢性病況、骨質疏鬆症、癌症,以及用於PWS或用於PWS之一或多種症狀。
Melanin-concentrating hormone (MCH) plays multiple roles in energy homeostasis and is central to the control of food intake and energy expenditure in the hypothalamus (Pissios et al., Endocr Rev 2006, 27(6):606-620). MCH has attracted much attention due to its effects on food intake and body weight, and its receptor MCHR1 remains one of the viable targets for obesity treatment (Pissios P., Peptides 2009, 30(11):2040-2044). MCH is one of the most potent central stimulants of feeding, regulating energy balance and mood (Pissios et al., Endocrinology 2003, 144(8):3514-3523; Pissios et al., Endocr Rev 2006, 27(6):606-620; Forray C., Curr Opin Pharmacol 2003, 3: 85-89; Qu et al., Nature 1996, 380: 243-47; Hervieu G., Expert Opin Ther Targets 2003, 7: 495-511; Chung et al., J Mol Neurosci 2011, 43:115-21). Prader-Willi syndrome (PWS) is a rare, complex neurodevelopmental genetic disorder caused by the absence of imprinted gene expression in the paternally derived region of chromosome 15q11.2-q13. PWS is the most common syndromic cause of life-threatening obesity, with an estimated prevalence of 1/10,000 to 1/25,000 live births, occurring equally in both males and females, and across ethnicities. The syndromic obesity caused by severe overeating is derived from the neurodevelopmental consequences of the small nucleolar C/D box RNA 116 (SNORD116) cluster deletion (which has been shown to be the smallest deleted region) that is always involved in cases of paternal copy deletion (Holm et al., Pediatrics 1993, 91:398-402; Gunay-Aygun et al., Pediatrics 2001, 108:E95; Duker et al., Eur. J. Hum. Genet. 2010;18:1196-201; de Smith et al., Hum. Mol. Genet. 2009, 18:3257-65; Bieth et al., Eur. J. Human Genet. 2015, 23:252-255; Polex-Wolf et al., J. Clin. Invest . 2018, 128:960-969; Tan et al., Genes 2020, 11:128; Chung et al., Open Biology 2020, 10:200195). Bulimia, a key behavioral symptom in PWS, has significant impacts on patient and caregiver well-being that go beyond weight gain alone. Management of binge eating is ranked as the highest priority among caregivers for PWS treatment goals. The uncontrolled appetite, weight gain, and impaired reproductive capacity of PWS may be explained by overactive MCH neurons due to a loss of "checks and balances" caused by a decrease in the amount of ORX in the lateral hypothalamus. Preventing MCH overactivity is most likely to improve MCH-ORX balance, which can ultimately help patients reduce symptoms related to eating. According to the latest preclinical reports, the MCH-MCHR1 system is overactive due to impaired ORX control, and PWS patients can benefit from MCHR1 antagonist treatment to control overeating and obesity (Pace M., JCI Insight 2020, 5:e137495; Pace et al., Hum. Mol. Genet. 2020, 29:2051-2064; Linehan et al., Mol. Meatabolism 2020, 36:100977; Linehan et al., J. Physiol 2022, 596:305-316). Therefore, MCHR1 antagonists may be used to treat diseases or conditions associated with melanin-concentrating
基於醫藥調配及病患投服目的,需要提供呈適用形式之化合物1。然而,在先前技術中未表示化合物1及其醫藥上可接受之鹽之固體形式,諸如晶形、共晶或僞多形體(pseudo-polymorph)/溶劑合物形(solvatomorph)特徵。For the purpose of pharmaceutical formulation and administration to patients, it is necessary to provide Compound 1 in a suitable form. However, the solid form of
多形性為化合物展現晶格中之分子排列不同的二或更多種不同結晶相之能力(J. Bernstein(2002) Polymorphism in molecular Crystals, Oxford Univ. Press. p. 2-4)。雖然多形體具有相同化學組成,但其堆積及幾何排列不同且展現不同物理性質,諸如熔點、X射線繞射圖、晶癖、密度、安定性、溶解度、機械性質(諸如硬度、壓實性(compactibility)、壓錠性質、流動、摻合)、流變參數等。Polymorphism is the ability of a compound to exhibit two or more different crystalline phases with different arrangements of the molecules in the crystal lattice (J. Bernstein (2002) Polymorphism in molecular Crystals, Oxford Univ. Press. p. 2-4). Although polymorphs have the same chemical composition, their packing and geometric arrangements are different and they exhibit different physical properties, such as melting point, X-ray diffraction pattern, crystal habit, density, stability, solubility, mechanical properties (such as hardness, compactibility, tableting properties, flow, mixing), rheological parameters, etc.
醫藥產業中進行廣泛研究以研發各種藥物物質之不同多形體(R. Hilfiker (ed. 2006) Polymorphism in the Pharmaceutical Industry, Wiley-VCH, p. 1-15),以獲得具有改良性能特徵之適宜的多形體或僞多形體。醫藥組成物之研發中對於活性成分的一般要求係活性成分具有適當的物理、物理化學及化學參數。此等參數之實例包含溶解度,特別是水溶度。於工業規模生產中應考慮的另一重要特徵係容易操作及良好單離性,其對於製程的經濟效益極為重要。另一重要態樣係活性成分之固體形式具有適當的物理及化學安定性,例如不吸濕,以及不顯著劣化。此外,給定之鹽的不同多形形式可具有不同固相特徵、物理及化學安定性。迄今,仍無可藉以清楚地預測給定之新化學實體的給定化合物可實體存在之不同固體形式的真實數目。此亦適用於預測關於給定形式之醫藥研發時需要考慮之所有複雜的物理及化學性質。因此,探索化合物之多形形貌及發現以及製造真實存在之固體形式仍然為實驗性挑戰,以及為醫藥領域中之重要的發明領域。極需要尋求具有有利醫藥性質之化合物的新固體形式。Extensive research is conducted in the pharmaceutical industry to develop different polymorphs of various drug substances (R. Hilfiker (ed. 2006) Polymorphism in the Pharmaceutical Industry, Wiley-VCH, p. 1-15) in order to obtain suitable polymorphs or pseudopolymorphs with improved performance characteristics. A general requirement for the active ingredient in the development of pharmaceutical compositions is that the active ingredient has appropriate physical, physicochemical and chemical parameters. Examples of such parameters include solubility, especially aqueous solubility. Another important characteristic to be considered in industrial-scale production is ease of handling and good isolation properties, which are extremely important for the economic efficiency of the process. Another important aspect is that the solid form of the active ingredient has appropriate physical and chemical stability, for example, it does not absorb moisture and does not deteriorate significantly. Furthermore, different polymorphic forms of a given salt may have different solid phase characteristics, physical and chemical stabilities. To date, there is no real number of different solid forms in which a given compound may exist that can be used to clearly predict a given new chemical entity. This also applies to predicting all the complex physical and chemical properties that need to be considered in pharmaceutical development for a given form. Therefore, exploring the polymorphic morphology of compounds and discovering and making solid forms that exist in reality remain experimental challenges and important areas of invention in the pharmaceutical field. There is a great need to find new solid forms of compounds with favorable pharmaceutical properties.
僞多形性為化合物與不同溶劑以二或更多種不同結晶相共存的能力。通常建議不要使用於結晶程序中可與特定化合物形成溶劑合物之溶劑來製造該化合物(Hilfiker等人(2019), Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development; p. 245-246; Wiley-VCH)。此外,除了用於醫藥研發之水合物以外,使用溶劑合形式非常不利,因為微量有機溶劑可能有害(Bhatia等人(2018), Dosage form design parameters, Chapter 2.2.2.: Crystal solvates and hydrates, Elsevier)。並且,已知溶劑合物形式顯示可變組成,可能提高重現性及長期安定性問題。Pseudopolymorphism is the ability of a compound to coexist in two or more different crystalline phases with different solvents. It is generally recommended not to use solvents that can form solvates with a particular compound during the crystallization process to make that compound (Hilfiker et al. (2019), Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development; p. 245-246; Wiley-VCH). In addition, with the exception of hydrates used in pharmaceutical development, the use of solvate forms is highly unfavorable because trace amounts of organic solvents can be harmful (Bhatia et al. (2018), Dosage form design parameters, Chapter 2.2.2.: Crystal solvates and hydrates, Elsevier). Furthermore, solvate forms are known to display variable composition, which may raise reproducibility and long-term stability issues.
國際專利申請案WO 2016/166684提供化合物1順丁烯二酸鹽之製備方法。WO 2016/166684實施例20(b)之重現實驗證實單離之結晶固體為乙醇溶劑合物,其不適於醫藥研發。International patent application WO 2016/166684 provides a method for preparing the maleic acid salt of
其他實驗證實化合物1之順丁烯二酸鹽顯示形成溶劑合形式之傾向提高,展現在不同有機溶劑如甲醇、乙醇、二氯甲烷、二甲亞碸等中之各式各樣僞多形體。該等溶劑合形式之共同特徵係溶劑含量增加(藉由熱重量分析(TGA)為高於1%)。形成新的多形體尤其是溶劑合物之傾向提高表示於儲存或醫藥調配期間多形體轉變或組成改變的風險。因此,於醫藥產品中使用化合物1之順丁烯二酸鹽是不利的。因此,需要提供適於醫藥調配及適於投服給人類之化合物1的改良形式。Other experiments confirmed that the maleic acid salt of
國際專利申請案WO 2016/166684亦提供將化合物1單離為游離鹼。重現實驗證實WO 2016/166684中之實施例20(a)的產物為具有不利的安定性性質之晶形,即,其為不適於醫藥研發之鹼的介穩晶形(形式B)。化合物1之形式B與大部分溶劑接觸時以及曝露於加熱時往往經歷多形體轉變。因而,於醫藥產品中使用化合物1形式B是不利的,且無法符合用於醫藥調配及用於有效抑制MCHR1且病患能忍受之治療的化合物1之適宜的固體形式之需求。International patent application WO 2016/166684 also provides for the isolation of
除了不利的順丁烯二酸鹽及鹼形式以外,先前技術中不曾描述化合物1之其他固體形式。Apart from the unfavorable maleate and base forms, no other solid forms of
因此,需要發現適於醫藥研發以及適於投服給需要與黑色素集中荷爾蒙受體1活性相關之疾病或病況的治療之病患且為此等病患能忍受的化合物1之新的固體形式或其醫藥上可接受之鹽。Therefore, there is a need to discover new solid forms of
本揭露內容係關於4-[(5-氯吡啶-2-基)甲氧基]-1-[3-(丙-2-基)-1H,2H,3H,4H,5H-[1,4]二氮呯并[1,7-a]吲哚-9-基]-1,2-二氫吡啶-2-酮(化合物1)之鹽酸鹽,其為可用於治療及/或預防肥胖症、肥胖症相關之共病病況及併發症、糖尿病、代謝失調、冠狀動脈疾病、腦血管疾病、周邊動脈疾病、高血壓、內分泌失調、精神疾患、人格障礙、飲食障礙、睡-醒周期障礙、物質濫用及成癮障礙、慢性肝臟及腎臟疾病、腸胃道疾病、肌肉骨骼系統之慢性病況、骨質疏鬆症、癌症、以及普威二氏症候群(PWS)或PWS之一或多種症狀的強效口服活性選擇性黑色素集中荷爾蒙受體1(MCHR1)拮抗劑。本揭露內容亦關於呈游離鹼形式之化合物1的安定晶形、關於其鹽酸鹽之安定晶形、製造相同固體形式之方法、其醫藥組成物、以及其治療應用。The present disclosure relates to the hydrochloride of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1H,2H,3H,4H,5H-[1,4]diazapenta[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one (Compound 1), which is useful for treating and/or preventing obesity, obesity-related comorbidities and complications, diabetes, metabolic disorders, coronary artery disease, Cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, mental illness, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic conditions of the musculoskeletal system, osteoporosis, cancer, and Prader-Willi syndrome (PWS) or one or more symptoms of PWS. The present disclosure also relates to a stable crystalline form of
如前文概述,發現化合物1順丁烯二酸鹽對於醫藥調配及對於有效抑制MCHR1且病患能忍受之治療是不利的。As outlined above, it was found that the maleate salt of Compound 1 is not suitable for pharmaceutical formulation and for the treatment of MCHR1 that is effective and tolerable to patients.
國際專利申請案WO 2016/166684提供化合物1順丁烯二酸鹽之製備方法(參考例1)。藉由XRPD(圖1)發現樣本為結晶的,但藉由TGA偵測有3.9%之顯著失重。WO 2016/166684實施例20(b)之重現實驗-參考例2-證實單離之結晶固體為乙醇溶劑合物(TGA:5.1%)。International patent application WO 2016/166684 provides a method for preparing the maleic acid salt of compound 1 (reference example 1). The sample was found to be crystalline by XRPD (Figure 1), but a significant weight loss of 3.9% was detected by TGA. The reproduction experiment of Example 20 (b) of WO 2016/166684 - reference example 2 - confirmed that the isolated crystalline solid was an ethanol solvent compound (TGA: 5.1%).
除了用於醫藥研發之水合物以外,使用溶劑合形式非常不利,因為微量溶劑可能有害(Bhatia等人(2018), Dosage form design parameters, Chapter 2.2.2.: Crystal solvates and hydrates, Elsevier)。並且,已知溶劑合物形式顯示可變組成,可能提高重現性及長期安定性問題。因此,溶劑合物通常不適於醫藥研發,並且通常建議不要使用於結晶程序中可與特定化合物形成溶劑合物之溶劑來製造該化合物(Hilfiker等人(2019), Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development; p. 245-246; Wiley-VCH)。With the exception of hydrates used in drug development, the use of solvate forms is highly unfavorable because trace amounts of solvent can be harmful (Bhatia et al. (2018), Dosage form design parameters, Chapter 2.2.2.: Crystal solvates and hydrates, Elsevier). Furthermore, solvate forms are known to exhibit variable composition, which may raise reproducibility and long-term stability issues. Therefore, solvates are generally not suitable for drug development, and it is generally recommended not to use solvents that can form solvates with a particular compound during the crystallization procedure to manufacture that compound (Hilfiker et al. (2019), Polymorphism in the Pharmaceutical Industry: Solid Form and Drug Development; p. 245-246; Wiley-VCH).
進行其他實驗以發現用於醫藥研發之化合物1順丁烯二酸鹽之適宜的多形體。從各種溶劑(例如甲醇、乙醇、二氯甲烷、二甲亞碸)以及藉由各種結晶方法(例如懸浮攪拌、冷卻、蒸發)之再結晶實驗係經設計且進行以識別化合物1順丁烯二酸鹽之安定且無溶劑多形體(參考例2-9)。於此等實驗中,識別數種晶形(圖1-9)但所有此等實驗中之殘餘溶劑含量(藉由TGA測定)均高於可接受限度,表示彼等為溶劑合物(圖10-17)。大量新的僞多形體結合高殘餘溶劑含量(藉由TGA為高於1%)表示於儲存或醫藥調配期間多形體轉變或組成改變的風險。因此,於醫藥產品中使用化合物1之順丁烯二酸鹽是不利的以及出現對於不同的更安定固體形式之需求。Other experiments were conducted to find suitable polymorphs of the maleate salt of
如前文概述,本發明係關於醫藥研發可接受之化合物1之安定結晶游離鹼及結晶鹽酸鹽。此說明亦關於該晶形之識別及製備方法。As summarized above, the present invention relates to a stable crystalline free base and crystalline hydrochloride salt of
結晶固相可藉由X射線繞射識別:粉末X射線繞射圖或一或多個繞射峰之位置為結晶材料之特徵。或者,振動光譜法,諸如IR及拉曼光譜法亦為用於區分不同多形/僞多形/非晶形之適宜且廣泛使用的方法。雖然振動光譜學主要探測局部、短程有序(分子內振動),但振動頻率亦受其周圍環境影響,使得該等頻率不只表示構形多形性,亦表示分子堆積之方式。因此,若以充足高波數解析度測量,不同多形體通常具有不同振動光譜(Hilfiker等人(2019), p. 418)。因此,藉由下列固態分析特徵中之一或多者可識別本發明之化合物1游離鹼及鹽酸鹽的各晶形以及與其他晶形區分:特徵XRPD繞射峰、IR吸收帶或拉曼峰。Crystalline solid phases can be identified by X-ray diffraction: the powder X-ray diffraction pattern or the position of one or more diffraction peaks is characteristic of crystalline materials. Alternatively, vibrational spectroscopy, such as IR and Raman spectroscopy, is also a suitable and widely used method for distinguishing different polymorphs/pseudopolymorphs/amorphous forms. Although vibrational spectroscopy mainly detects local, short-range order (intramolecular vibrations), the vibrational frequencies are also affected by their surroundings, making them indicative not only of the configurational polymorphism, but also of the way the molecules are stacked. Therefore, different polymorphs usually have different vibrational spectra if measured with sufficiently high wavenumber resolution (Hilfiker et al. (2019), p. 418). Therefore, each crystalline form of the free base and hydrochloride of
本發明之一態樣為化合物1之鹽酸鹽。該鹽可以各種形式諸如油或固體存在。該固體可為非晶、結晶或二者之混合。One aspect of the present invention is a hydrochloride of
於另一態樣中,本發明提供化合物1鹽酸鹽之製備方法,其包含:
a)提供化合物1於任何適宜的溶劑中之溶液;
b)混合步驟a)中之該溶液與鹽酸溶液
c)攪動該漿料;以及
d)單離化合物1鹽酸鹽。
In another embodiment, the present invention provides a method for preparing
步驟a)中所使用之溶劑係選自由下列所組成之群組:水、甲醇、乙醇、異丙醇、2-丙醇、1-丁醇、三級丁醇、1-戊醇、2-戊醇、丙酮、丁酮、2-戊酮、3-戊酮、甲基丁基酮、甲基乙基酮、甲基異丁基酮、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級丁酯、乙酸異丁酯、二氯甲烷、二氯化乙烯、乙腈、四氫呋喃、1,4-二㗁烷、2-甲氧基乙醇、二乙醚、二異丙醚、甲基三級丁基醚或其混合物。The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.
步驟b)中所使用之溶劑係選自由下列所組成之群組:水、甲醇、乙醇、異丙醇、2-丙醇、1-丁醇、三級丁醇、1-戊醇、2-戊醇、丙酮、丁酮、2-戊酮、3-戊酮、甲基丁基酮、甲基乙基酮、甲基異丁基酮、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級丁酯、乙酸異丁酯、二氯甲烷、二氯化乙烯、乙腈、四氫呋喃、1,4-二㗁烷、2-甲氧基乙醇、二乙醚、二異丙醚、甲基三級丁基醚或其混合物。The solvent used in step b) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.
步驟c)涉及在任何適宜的溫度,包含回流、室溫、0-5℃或任何其他適宜的溫度下,藉由任何適宜的技術,包含攪拌棒、攪拌桿或搖動器攪動漿料。Step c) involves stirring the slurry at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature, by any suitable technique, including a stir bar, a stirring rod or a shaker.
產物之單離可藉由在環境條件下或在惰性氣氛(例如氮)中進行。產物為白色或米白色固體。The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.
本發明之另一態樣為化合物1之鹽酸鹽之安定無水物形式,形式A。Another aspect of the present invention is a stable anhydrate form of the hydrochloride salt of
本發明之另一態樣為化合物1之鹽酸鹽,包含至少5%、至少10%、至少20%、至少40%、至少60%、至少80%、至少90%、至少95%、至少99%之化合物1鹽酸鹽形式A。Another aspect of the invention is a hydrochloride salt of
化合物1鹽酸鹽形式A之X射線繞射圖係顯示於圖18。詳細峰列表係顯示於表1。化合物1鹽酸鹽形式A之最具特徵峰係在9.2、12.5、14.5、15.1、15.8、17.4±0.2° 2θ。
The X-ray diffraction pattern of
化合物1鹽酸鹽形式A亦可以其FT-IR光譜表示特徵。化合物1鹽酸鹽形式A之紅外線光譜係顯示於圖19。化合物1鹽酸鹽形式A之吸收帶的詳細列表係顯示於表2。化合物1鹽酸鹽形式A之最具特徵吸收帶係在2474、2524、1668、1479及1222±4 cm
-1。
化合物1鹽酸鹽形式A亦可以其拉曼光譜表示特徵。化合物1鹽酸鹽形式A之拉曼光譜係顯示於圖20。化合物1鹽酸鹽形式A之拉曼峰的詳細列表係顯示於表3。化合物1鹽酸鹽形式A之最具特徵拉曼峰係在1549、1344、1303、1257及747cm
-1。
化合物1鹽酸鹽形式A亦可以其微差掃描熱量法(DSC)溫度記錄圖表示特徵。化合物1鹽酸鹽形式A之典型DSC溫度記錄圖係顯示於圖21。化合物1鹽酸鹽形式A於分解期間熔融,具有寬吸熱DSC峰且峰最大值介於250與300℃。
化合物1鹽酸鹽形式A係藉由如圖22顯示之其熱重量(TGA)溫度記錄圖證實為真正無水物形式。化合物1鹽酸鹽形式A之失重少於1.0%(高達175℃)。
化合物1鹽酸鹽形式A之化學安定性係經由如表4中所示之一組強制安定性(forced stability)研究來評估。化合物1鹽酸鹽形式A之樣本係在不同的經控制條件(50℃乾燥、75℃乾燥及50℃ 85% RH)下儲存10天,以及以與初始樣本相同方法分析。
The chemical stability of
化合物1鹽酸鹽形式A之樣本的雜質曲線、乾燥時之損失及多形體形式於強制安定性研究期間未改變,證實化合物1鹽酸鹽形式A於50℃、75℃及於50℃ 85% RH可安定達10天。The impurity profile, loss on drying, and polymorphic form of samples of
術語溶解度係用以測量可溶解於1 L之模擬溶劑中的化合物1鹽酸鹽之量(以μmol計)。模擬溶劑包含FaSSiF(禁食狀態模擬腸液)及FeSSiF(進食狀態模擬腸液)。當最高濃度為在37±1℃可溶於250 mL或更少之pH範圍為1-6.8的水性介質中時,根據生物醫藥分類系統(BCS),藥物物質被視為高度可溶(Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System, Guidance for Industry, December 2017, https://www.gmp-compliance.org)。The term solubility is used to measure the amount of
FaSSiF及FeSSiF溶液中之化合物1 HCl形式A的溶解度數據如表5所示。於模擬流體(FaSSiF及FeSSiF)中,化合物1 HCl形式A高度可溶至高達20 mg濃度。
The solubility data of
上述分析及物理表徵分析證實化合物1鹽酸鹽形式A為高度可溶於模擬介質之化合物1鹽酸鹽之安定無水物多形體。其在正常條件(高達70% RH)不吸濕,但於高濕度下需要一些防護措施。分析結果表示該固體形式適於醫藥研發。The above analysis and physical characterization analysis confirmed that
於另一態樣中,本發明提供化合物1鹽酸鹽形式A之製備方法,其包含:
a)提供化合物1鹽酸鹽於任何適宜的溶劑中之溶液;
b)使部分該溶劑蒸發以獲得懸浮液;以及
c)攪動該漿料;以及
d)單離化合物1鹽酸鹽形式A。
In another embodiment, the present invention provides a method for preparing
步驟a)中所提供之溶液可藉由將化合物1鹽酸鹽溶解或藉由在溶液中混合化合物1與適當量之鹽酸所提供。The solution provided in step a) can be provided by dissolving
步驟a)中所使用之溶劑係選自由下列所組成之群組:水、甲醇、乙醇、異丙醇、2-丙醇、1-丁醇、三級丁醇、1-戊醇、2-戊醇、丙酮、丁酮、2-戊酮、3-戊酮、甲基丁基酮、甲基乙基酮、甲基異丁基酮、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級丁酯、乙酸異丁酯、二氯甲烷、二氯化乙烯、乙腈、四氫呋喃、1,4-二㗁烷、2-甲氧基乙醇、二乙醚、二異丙醚、甲基三級丁基醚或其混合物。The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.
步驟b)涉及藉由任何適宜的技術蒸發溶劑,包含旋轉蒸餾裝置,諸如旋轉蒸發器、開放式反應器或任何其他適宜的技術。蒸發可藉由升高溫度或藉由降低壓力或其組合引發。Step b) involves evaporating the solvent by any suitable technique, including a rotary distillation apparatus such as a rotary evaporator, an open reactor or any other suitable technique. Evaporation can be induced by increasing the temperature or by reducing the pressure or a combination thereof.
步驟c)涉及在任何適宜的溫度,包含回流、室溫、0-5℃或任何其他適宜的溫度下,藉由任何適宜的技術,包含攪拌棒、攪拌桿或搖動器攪動漿料。Step c) involves stirring the slurry at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature, by any suitable technique, including a stir bar, a stirring rod or a shaker.
產物之單離可藉由在環境條件下或在惰性氣氛(例如氮)中進行。產物為白色或米白色固體。The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.
於另一態樣中,本發明提供化合物1鹽酸鹽形式A之製備方法,其包含:
a)提供化合物1鹽酸鹽於任何適宜的溶劑中之溶液;
b)使該溶液冷卻以獲得漿料;以及
c)攪動該漿料;以及
d)單離化合物1鹽酸鹽形式A。
In another embodiment, the present invention provides a method for preparing
步驟a)中所提供之溶液可藉由將化合物1鹽酸鹽溶解或藉由在溶液中混合化合物1與適當量之鹽酸所提供。The solution provided in step a) can be provided by dissolving
步驟a)中所使用之溶劑係選自由下列所組成之群組:水、甲醇、乙醇、異丙醇、2-丙醇、1-丁醇、三級丁醇、1-戊醇、2-戊醇、丙酮、丁酮、2-戊酮、3-戊酮、甲基丁基酮、甲基乙基酮、甲基異丁基酮、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級丁酯、乙酸異丁酯、二氯甲烷、二氯化乙烯、乙腈、四氫呋喃、1,4-二㗁烷、2-甲氧基乙醇、二乙醚、二異丙醚、甲基三級丁基醚或其混合物。The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.
溶液之溫度可為任何適宜的溫度,例如溶劑之回流溫度、50℃、40℃、室溫等。The temperature of the solution may be any suitable temperature, such as the reflux temperature of the solvent, 50°C, 40°C, room temperature, etc.
步驟b)涉及使溶液冷卻至低於步驟a)之溫度,例如冷卻至室溫或0-5℃或任何適宜的溫度。Step b) involves cooling the solution to a temperature lower than that of step a), for example to room temperature or 0-5°C or any suitable temperature.
步驟c)涉及在步驟b)所設定之溫度或低於步驟b)所設定之溫度藉由任何適宜的技術,包含攪拌棒、攪拌桿或搖動器攪動漿料。Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique, including a stir bar, a stirring rod or a shaker.
產物之單離可藉由在環境條件下或在惰性氣氛(例如氮)中進行。產物為白色或米白色固體。The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.
於另一態樣中,本發明提供化合物1鹽酸鹽形式A之製備方法,其包含:
a)提供化合物1鹽酸鹽於任何適宜的溶劑中之溶液;
b)混合該溶液與反溶劑以獲得漿料;以及
c)攪動該漿料;以及
d)單離化合物1鹽酸鹽形式A。
In another embodiment, the present invention provides a method for preparing
步驟a)中所使用之溶劑及步驟b)中之反溶劑係選自由下列所組成之群組:水、甲醇、乙醇、異丙醇、2-丙醇、1-丁醇、三級丁醇、1-戊醇、2-戊醇、丙酮、丁酮、2-戊酮、3-戊酮、甲基丁基酮、甲基乙基酮、甲基異丁基酮、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級丁酯、乙酸異丁酯、二氯甲烷、二氯化乙烯、乙腈、四氫呋喃、1,4-二㗁烷、2-甲氧基乙醇、二乙醚、二異丙醚、甲基三級丁基醚或其混合物。The solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.
溶液之溫度可為任何適宜的溫度,例如溶劑之回流溫度、50℃、40℃、室溫等。The temperature of the solution may be any suitable temperature, such as the reflux temperature of the solvent, 50°C, 40°C, room temperature, etc.
於步驟b)中混合溶液可藉由將溶液配料至反溶劑或藉由將反溶劑配料至溶液來進行。配料可不經控制或藉由任何適宜的技術控制。Mixing the solutions in step b) can be performed by dosing the solution into the antisolvent or by dosing the antisolvent into the solution. Dosing can be uncontrolled or controlled by any suitable technique.
步驟c)涉及在步驟b)所設定之溫度或低於步驟b)所設定之溫度藉由任何適宜的技術,包含攪拌棒、攪拌桿或搖動器攪動漿料。Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique, including a stir bar, a stirring rod or a shaker.
產物之單離可藉由在環境條件下或在惰性氣氛(例如氮)中進行。產物為白色或米白色固體。The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.
國際專利申請案WO 2016/166684亦提供將化合物1單離為游離鹼。參考例10證實如WO 2016/166684中之實施例20(a)所述之溶析液的蒸發製造化合物1游離鹼之晶形,形式B。化合物1形式B之分析表徵,尤其是DSC分析揭露此形式於較高溫度經歷多形體轉變,以及形成熔點介於200與210℃之新形式。此等DSC結果表示化合物1游離鹼形式B可能不為化合物1游離鹼之安定多形體。International patent application WO 2016/166684 also provides for the isolation of
根據Ostwald階段法則(Ostwald's rule of stages)(Ostwald, 1897)陳述於結晶中,系統透過自由能之最小變化從初始高能狀態移至平衡,因此暗示可以任何結晶作用先單離至少安定的多形體(Jonathan C. Burley, Melinda J. Duer, Robin S. Stein, Ranko M. Vrcelj, European Journal of Pharmaceutical Sciences, Volume 31, Issue 5, August 2007, Pages 271-276)。為了獲得更安定的多形體,設計且使用更受控制之結晶程序進行進一步結晶實驗(例如實施例3):應用額外的再懸浮步驟代替快速蒸發溶析液。於實施例3中,獲得具有一些微量形式B之化合物1游離鹼的新多形體形式A。於進一步結晶實驗中,製備純形式A以及表示特徵。According to Ostwald's rule of stages (Ostwald, 1897), in crystallization, the system moves from an initial high-energy state to equilibrium with minimal change in free energy, thus suggesting that the least stable polymorph can be isolated first in any crystallization (Jonathan C. Burley, Melinda J. Duer, Robin S. Stein, Ranko M. Vrcelj, European Journal of Pharmaceutical Sciences, Volume 31,
本發明之另一態樣為化合物1游離鹼之安定無水物形式,形式A。Another aspect of the present invention is the stable anhydrate form of the free base of
本發明之另一態樣為化合物1游離鹼之結晶固體形式,包含至少5%、至少10%、至少20%、至少40%、至少60%、至少80%、至少90%、至少95%、至少99%之化合物1游離鹼形式A。Another aspect of the invention is a crystalline solid form of
化合物1游離鹼形式A之X射線繞射圖顯示於圖23。詳細峰列表係顯示於表6。化合物1游離鹼形式A之最具特徵峰係在5.9、17.7、18.1、19.8及22.2° 2θ。
The X-ray diffraction pattern of
化合物1游離鹼形式A亦可以其FT-IR光譜表示特徵。化合物1游離鹼形式A之紅外線光譜係顯示於圖24。化合物1游離鹼形式A之吸收帶的詳細列表係顯示於表7。化合物1游離鹼形式A之最具特徵吸收帶係在1663、1478、1220、860、795及766±4 cm
-1。
化合物1游離鹼形式A亦可以其拉曼光譜表示特徵。化合物1游離鹼形式A之拉曼光譜係顯示於圖25。化合物1游離鹼形式A之拉曼峰的詳細列表係顯示於表8。化合物1游離鹼形式A之最具特徵拉曼峰係在1554、1345、1267、1260及750±4 cm
-1。
化合物1游離鹼形式A亦可以其DSC溫度記錄圖表示特徵。化合物1游離鹼形式A之典型DSC溫度記錄圖係顯示於圖26。化合物1游離鹼形式A展現單一熔融吸熱,其開始溫度值介於200與210℃。
化合物1游離鹼形式A係藉由如圖27顯示之其TGA溫度記錄圖證實為真正無水物形式。化合物1游離鹼形式A之失重少於0.5%(高達215℃)。
化合物1游離鹼形式A之化學安定性係經由如表9中所示之一組強制安定性研究來評估。化合物1游離鹼形式A之樣本係在不同的經控制條件(50℃乾燥、75℃乾燥及50℃ 85% RH)下儲存10天,以及以與初始樣本相同方法分析。
The chemical stability of
化合物1游離鹼形式A之樣本的雜質曲線、乾燥時之損失及多形體形式於強制安定性研究期間未改變,證實化合物1鹽酸鹽形式A於50℃、75℃及於50℃ 85% RH可安定達10天。The impurity profile, loss on drying, and polymorphic forms of samples of
化合物1游離鹼形式A於PBS、FaSSiF及FeSSiF溶液中之溶解度係如表10所示。化合物1 HCl形式A為高達9 mg濃度之高度可溶,但於更酸性介質中,溶解度又更高。
The solubility of
上述分析及物理表徵分析證實化合物1游離鹼形式A為化合物1游離鹼之安定的非吸濕性無水物多形體,其於模擬介質中顯示可接受之溶解度。分析結果表示該固體形式適於醫藥研發。The above analysis and physical characterization analysis confirmed that
於另一態樣中,本發明提供化合物1游離鹼形式A之製備方法,其包含:
a)提供化合物1游離鹼於任何適宜的溶劑中之溶液;
b)使部分該溶劑蒸發以獲得懸浮液;以及
c)攪動該漿料;以及
d)單離化合物1游離鹼形式A。
In another embodiment, the present invention provides a method for preparing
步驟a)中所使用之溶劑係選自由下列所組成之群組:水、甲醇、乙醇、異丙醇、2-丙醇、1-丁醇、三級丁醇、1-戊醇、2-戊醇、丙酮、丁酮、2-戊酮、3-戊酮、甲基丁基酮、甲基乙基酮、甲基異丁基酮、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級丁酯、乙酸異丁酯、二氯甲烷、二氯化乙烯、乙腈、四氫呋喃、1,4-二㗁烷、2-甲氧基乙醇、二乙醚、二異丙醚、甲基三級丁基醚或其混合物。The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.
步驟b)涉及藉由任何適宜的技術蒸發溶劑,包含旋轉蒸餾裝置,諸如旋轉蒸發器、開放式反應器或任何其他適宜的技術。蒸發可藉由升高溫度或藉由降低壓力或其組合引發。Step b) involves evaporating the solvent by any suitable technique, including a rotary distillation apparatus such as a rotary evaporator, an open reactor or any other suitable technique. Evaporation can be induced by increasing the temperature or by reducing the pressure or a combination thereof.
步驟c)涉及在任何適宜的溫度,包含回流、室溫、0-5℃或任何其他適宜的溫度下,藉由任何適宜的技術,包含攪拌棒、攪拌桿或搖動器攪動漿料。Step c) involves stirring the slurry at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature, by any suitable technique, including a stir bar, a stirring rod or a shaker.
產物之單離可藉由在環境條件下或在惰性氣氛(例如氮)中進行。產物為白色或米白色固體。The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.
於另一態樣中,本發明提供化合物1游離鹼形式A之製備方法,其包含:
a)提供化合物1游離鹼於任何適宜的溶劑中之溶液;
b)使該溶液冷卻以獲得漿料;以及
c)攪動該漿料;以及
d)單離化合物1游離鹼形式A。
In another embodiment, the present invention provides a method for preparing
步驟a)中所使用之溶劑係選自由下列所組成之群組:水、甲醇、乙醇、異丙醇、2-丙醇、1-丁醇、三級丁醇、1-戊醇、2-戊醇、丙酮、丁酮、2-戊酮、3-戊酮、甲基丁基酮、甲基乙基酮、甲基異丁基酮、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級丁酯、乙酸異丁酯、二氯甲烷、二氯化乙烯、乙腈、四氫呋喃、1,4-二㗁烷、2-甲氧基乙醇、二乙醚、二異丙醚、甲基三級丁基醚或其混合物。The solvent used in step a) is selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.
溶液之溫度可為任何適宜的溫度,例如溶劑之回流溫度、50℃、40℃、室溫等。The temperature of the solution may be any suitable temperature, such as the reflux temperature of the solvent, 50°C, 40°C, room temperature, etc.
步驟b)涉及使溶液冷卻至低於步驟a)之溫度,例如冷卻至室溫或0-5℃或任何適宜的溫度。Step b) involves cooling the solution to a temperature lower than that of step a), for example to room temperature or 0-5°C or any suitable temperature.
步驟c)涉及在步驟b)所設定之溫度或低於步驟b)所設定之溫度藉由任何適宜的技術,包含攪拌棒、攪拌桿或搖動器攪動漿料。Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique, including a stir bar, a stirring rod or a shaker.
產物之單離可藉由在環境條件下或在惰性氣氛(例如氮)中進行。產物為白色或米白色固體。The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.
於另一態樣中,本發明提供化合物1游離鹼形式A之製備方法,其包含:
a)提供化合物1游離鹼之固體形式於任何適宜的溶劑中之懸浮液;
b)攪動漿料;以及
c)單離化合物1形式A。
In another embodiment, the present invention provides a method for preparing
於步驟a)中,化合物1游離鹼之固體形式可為形式B或形式D或形式A或其任何混合物。步驟a)中所使用之溶劑係選自由下列所組成之群組:水、甲醇、乙醇、異丙醇、2-丙醇、1-丁醇、三級丁醇、1-戊醇、2-戊醇、丙酮、丁酮、2-戊酮、3-戊酮、甲基丁基酮、甲基乙基酮、甲基異丁基酮、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級丁酯、乙酸異丁酯、二氯甲烷、二氯化乙烯、乙腈、四氫呋喃、1,4-二㗁烷、2-甲氧基乙醇、二乙醚、二異丙醚、甲基三級丁基醚或其混合物。In step a), the solid form of the free base of
步驟b)涉及在任何適宜的溫度,包含回流、室溫、0-5℃或任何其他適宜的溫度下,藉由任何適宜的技術,包含攪拌棒、攪拌桿或搖動器攪動漿料。Step b) involves stirring the slurry at any suitable temperature, including reflux, room temperature, 0-5°C or any other suitable temperature, by any suitable technique, including a stir bar, a stirring rod or a shaker.
產物之單離可藉由在環境條件下或在惰性氣氛(例如氮)中進行。產物為白色或米白色固體。The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.
於另一態樣中,本發明提供化合物1游離鹼形式A之製備方法,其包含:
a)提供化合物1游離鹼於任何適宜的溶劑中之溶液;
b)混合該溶液與反溶劑以獲得漿料;以及
c)攪動該漿料;以及
d)單離化合物1游離鹼形式A。
In another embodiment, the present invention provides a method for preparing
步驟a)中所使用之溶劑及步驟b)中之反溶劑係選自由下列所組成之群組:甲醇、乙醇、異丙醇、2-丙醇、1-丁醇、三級丁醇、1-戊醇、2-戊醇、丙酮、丁酮、2-戊酮、3-戊酮、甲基丁基酮、甲基乙基酮、甲基異丁基酮、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級丁酯、乙酸異丁酯、二氯甲烷、二氯化乙烯、乙腈、四氫呋喃、1,4-二㗁烷、2-甲氧基乙醇、二乙醚、二異丙醚、甲基三級丁基醚或其混合物。The solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.
溶液之溫度可為任何適宜的溫度,例如溶劑之回流溫度、50℃、40℃、室溫等。The temperature of the solution may be any suitable temperature, such as the reflux temperature of the solvent, 50°C, 40°C, room temperature, etc.
於步驟b)中混合溶液可藉由將溶液配料至反溶劑或藉由將反溶劑配料至溶液來進行。配料可不經控制或藉由任何適宜的技術控制。Mixing the solutions in step b) can be performed by dosing the solution into the antisolvent or by dosing the antisolvent into the solution. Dosing can be uncontrolled or controlled by any suitable technique.
步驟c)涉及在步驟b)所設定之溫度或低於步驟b)所設定之溫度藉由任何適宜的技術,包含攪拌棒、攪拌桿或搖動器攪動漿料。Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique, including a stir bar, a stirring rod or a shaker.
產物之單離可藉由在環境條件下或在惰性氣氛(例如氮)中進行。產物為白色或米白色固體。The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.
於另一態樣中,本發明提供化合物1游離鹼形式B之製備方法,其包含:
a)提供化合物1游離鹼於任何適宜的溶劑中之溶液;
b)混合該溶液與反溶劑以獲得漿料;以及
d)單離化合物1形式A。
In another embodiment, the present invention provides a method for preparing
步驟a)中所使用之溶劑及步驟b)中之反溶劑係選自由下列所組成之群組:水、甲醇、乙醇、異丙醇、2-丙醇、1-丁醇、三級丁醇、1-戊醇、2-戊醇、丙酮、丁酮、2-戊酮、3-戊酮、甲基丁基酮、甲基乙基酮、甲基異丁基酮、甲酸乙酯、乙酸甲酯、乙酸乙酯、乙酸丙酯、乙酸三級丁酯、乙酸異丁酯、二氯甲烷、二氯化乙烯、乙腈、四氫呋喃、1,4-二㗁烷、2-甲氧基乙醇、二乙醚、二異丙醚、甲基三級丁基醚或其混合物。The solvent used in step a) and the anti-solvent in step b) are selected from the group consisting of water, methanol, ethanol, isopropanol, 2-propanol, 1-butanol, tert-butanol, 1-pentanol, 2-pentanol, acetone, butanone, 2-pentanone, 3-pentanone, methyl butyl ketone, methyl ethyl ketone, methyl isobutyl ketone, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, tert-butyl acetate, isobutyl acetate, dichloromethane, ethylene dichloride, acetonitrile, tetrahydrofuran, 1,4-dioxane, 2-methoxyethanol, diethyl ether, diisopropyl ether, methyl tert-butyl ether or a mixture thereof.
溶液之溫度可為任何適宜的溫度,例如溶劑之回流溫度、50℃、40℃、室溫等。The temperature of the solution may be any suitable temperature, such as the reflux temperature of the solvent, 50°C, 40°C, room temperature, etc.
於步驟b)中混合溶液可藉由將溶液配料至反溶劑或藉由將反溶劑配料至溶液來進行。配料可不經控制或藉由任何適宜的技術控制。Mixing the solutions in step b) can be performed by dosing the solution into the antisolvent or by dosing the antisolvent into the solution. Dosing can be uncontrolled or controlled by any suitable technique.
產物之單離可藉由在環境條件下或在惰性氣氛(例如氮)中進行。產物為白色或米白色固體。The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.
化合物1形式B之X射線繞射圖顯示於圖28。詳細峰列表係顯示於表11。化合物1形式B之最具特徵峰係在6.1、16.0、18.0、19.2及21.5±0.2° 2θ。
The X-ray diffraction pattern of
化合物1形式B亦可以其FT-IR光譜表示特徵。形式B之紅外線光譜係顯示於圖29。化合物1形式B之吸收帶的詳細列表係顯示於表12。
化合物1形式B亦可以其拉曼光譜表示特徵。化合物1形式B之拉曼光譜係顯示於圖30。化合物1形式B之拉曼峰的詳細列表係顯示於表13。
化合物1形式B亦可以其DSC溫度記錄圖表示特徵。化合物1形式B之典型DSC溫度記錄圖係顯示於圖31。化合物1形式B在介於200與210℃開始的熔融吸熱之前展現介於100與200℃之寬放熱。
於另一態樣中,本發明提供化合物1游離鹼之吡啶溶劑合物形式C之製備方法,其係藉由將化合物1順丁烯二酸鹽懸浮於吡啶中、攪動及單離呈白色或米白色固體化合物1游離鹼形式C。攪動涉及在任何適宜的溫度,包含回流、室溫、0-5℃或任何其他適宜的溫度下,藉由任何適宜的技術,包含攪拌棒、攪拌桿或搖動器攪動漿料。In another aspect, the present invention provides a method for preparing a pyridine solvent complex of
化合物1游離鹼形式C之X射線繞射圖係顯示於圖32。詳細峰列表係顯示於表14。化合物1游離鹼形式C之最具特徵峰係在2.6、5.3、16.0、19.4及24.7±0.2° 2θ。
The X-ray diffraction pattern of
化合物1游離鹼形式C亦可以其DSC溫度記錄圖表示特徵。化合物1游離鹼形式C之典型DSC溫度記錄圖係顯示於圖33。化合物1游離鹼形式C在介於200與210℃開始的熔融吸熱之前展現介於50與150℃之寬吸熱。
化合物1游離鹼形式C之典型TGA溫度記錄圖係顯示於圖34。形式C之失重為至120℃約10%。A typical TGA thermogram of
本發明之另一態樣為化合物1游離鹼水合物形式,形式D。Another aspect of the present invention is the free base hydrate form of
本發明之另一態樣為化合物1游離鹼之結晶固體形式,包含至少5%、至少10%、至少20%、至少40%、至少60%、至少80%、至少90%、至少95%、至少99%之化合物1游離鹼形式D。Another aspect of the invention is a crystalline solid form of
化合物1游離鹼形式D之X射線繞射圖顯示於圖35。詳細峰列表係顯示於表15。化合物1游離鹼形式D之最具特徵峰係在8.1、18.4、18.8、19.0及20.4±0.2° 2θ。
The X-ray diffraction pattern of
化合物1游離鹼形式D亦可以其FT-IR光譜表示特徵。形式D之紅外線光譜係顯示於圖36。化合物1游離鹼形式D之吸收帶的詳細列表係顯示於表15。化合物1游離鹼形式D之最具特徵吸收帶係在3515、3243、2869、2829及1650±4 cm
-1。
化合物1游離鹼形式D亦可以其拉曼光譜表示特徵。形式D之拉曼光譜係顯示於圖37。化合物1游離鹼形式D之拉曼峰的詳細列表係顯示於表16。化合物1游離鹼形式D之最具特徵拉曼峰係在1644、1552、1539、1301、1257±4 cm
-1。
化合物1游離鹼形式D亦可以其DSC溫度記錄圖表示特徵。化合物1游離鹼形式D之典型DSC溫度記錄圖係顯示於圖38。化合物1游離鹼形式D在介於200與210℃開始的熔融吸熱之前展現介於50與110℃之寬吸熱。
化合物1游離鹼形式D為水合物形式,其TGA溫度記錄圖展現介於50與110℃為4.1%之特徵失重。化合物1游離鹼形式D之典型TGA溫度記錄圖係顯示於圖39。樣本之含水量係藉由Karl Fisher滴定確認(4.6%)。
於另一態樣中,本發明提供化合物1游離鹼形式D之製備方法,其包含:
a)提供化合物1游離鹼於任何適宜的溶劑中之溶液;
b)混合該溶液與水以獲得漿料;以及
c)攪動該漿料;以及
d)單離化合物1游離鹼形式D。
In another embodiment, the present invention provides a method for preparing
步驟a)中所使用之溶劑係選自由下列所組成之群組:甲醇、乙醇、異丙醇、2-丙醇、丙酮、丁酮、2-戊酮、3-戊酮、乙腈、四氫呋喃、2-甲氧基乙醇、或其混合物。The solvent used in step a) is selected from the group consisting of methanol, ethanol, isopropanol, 2-propanol, acetone, butanone, 2-pentanone, 3-pentanone, acetonitrile, tetrahydrofuran, 2-methoxyethanol, or a mixture thereof.
溶液之溫度可為任何適宜的溫度,例如溶劑之回流溫度、50℃、40℃、室溫等。The temperature of the solution may be any suitable temperature, such as the reflux temperature of the solvent, 50°C, 40°C, room temperature, etc.
於步驟b)中混合溶液可藉由將溶液配料至反溶劑或藉由將反溶劑配料至溶液來進行。配料可不經控制或藉由任何適宜的技術控制。Mixing the solutions in step b) can be performed by dosing the solution into the antisolvent or by dosing the antisolvent into the solution. Dosing can be uncontrolled or controlled by any suitable technique.
步驟c)涉及在步驟b)所設定之溫度或低於步驟b)所設定之溫度藉由任何適宜的技術,包含攪拌棒、攪拌桿或搖動器攪動漿料。Step c) involves stirring the slurry at or below the temperature set in step b) by any suitable technique, including a stir bar, a stirring rod or a shaker.
產物之單離可藉由在環境條件下或在惰性氣氛(例如氮)中進行。產物為白色或米白色固體。The product can be isolated under ambient conditions or in an inert atmosphere (such as nitrogen). The product is a white or off-white solid.
為進行分析研究,使用下列實驗條件: FT-IR光譜法測量之參數: 儀器: Thermo-Nicolet 6700 相: KBr丸粒 光譜解析度: 4 cm -1偵測器: DTGS 分光鏡: XT-KBr 鏡移動速度: 0.6329 掃描次數: 100 FT-拉曼光譜法測量之參數: 儀器: Thermo-Nicolet NXR9650 測量範圍: 3500至200 cm -1光譜解析度: 4 cm -1偵測器: Ge 分光鏡: CaF 2鏡移動速度: 0.1581 掃描次數: 256 雷射性能: 500 mW X射線粉末繞射測量之參數: 儀器: PANanalytical X’Pert PRO MPD 輻射: CuKα 加速電壓: 40 kV 陽極電流: 40 mA 測角儀: PW3050/60 掃描速度: 0.0305 s 增量: 0.0131° 試樣架: PW1818/25 & 40(透射,樣本在箔之間) 試樣架旋轉器: PW3064/60(反射/透射旋轉器) 試樣架之旋轉速度: 1轉/秒 偵測器: PIXcel(PW3018/00) 2θ測量之不確定性: ±0.2° TGA測量之參數: 儀器: TA Instruments TGA Q5000或Discovery TGA 5500 加熱速率: 10℃/min 樣本重量: ~2至10 mg 氣氛: 60 mL/min N 2DSC測量之參數: 儀器: TA Instruments DSC Q1000或Discovery DSC 2500 加熱速率: 10℃/min 樣本重量: ~1至3 mg 盤類型: 開放式Al盤 氣氛: 50 mL/min N 2 溶解度之分析方法 For the analytical studies the following experimental conditions were used: Parameters for FT-IR spectroscopy measurements: Instrument: Thermo-Nicolet 6700 Phase: KBr pellets Spectral resolution: 4 cm -1 Detector: DTGS Spectroscope: XT-KBr Mirror movement speed: 0.6329 Number of scans: 100 Parameters for FT-Raman spectroscopy measurements: Instrument: Thermo-Nicolet NXR9650 Measuring range: 3500 to 200 cm -1 Spectral resolution: 4 cm -1 Detector: Ge Spectroscope: CaF 2 Mirror movement speed: 0.1581 Number of scans: 256 Laser performance: 500 mW Parameters for X-ray powder diffraction measurements: Instrument: PANanalytical X'Pert PRO MPD Radiation: CuKα Accelerating voltage: 40 kV Anode current: 40 mA Goniometer: PW3050/60 Scanning speed: 0.0305 s Increment: 0.0131° Sample holder: PW1818/25 & 40 (transmission, sample between foils) Sample holder rotator: PW3064/60 (reflection/transmission rotator) Sample holder rotation speed: 1 rev/sec Detector: PIXcel (PW3018/00) Uncertainty of 2θ measurement: ±0.2° Parameters for TGA measurement: Instrument: TA Instruments TGA Q5000 or Discovery TGA 5500 Heating rate: 10°C/min Sample weight: ~2 to 10 mg Atmosphere: 60 mL/min N 2 DSC measurement parameters: Instrument: TA Instruments DSC Q1000 or Discovery DSC 2500 Heating rate: 10℃/min Sample weight: ~1 to 3 mg Pan type: Open Al pan Atmosphere: 50 mL/min N 2 Solubility analysis method
在透明試驗容器中秤重大約2-2 mg(N=5)之試驗物質以及於其中添加300 μL之溶劑。將試驗容器置於機械式搖動器且於37℃搖動24 h之培育時間,過濾且藉由HPLC-MS(Agilent1200液相層析儀,耦合6410 QQQ-MS,Kinetex EVO C18管柱)測定濾液中之化合物1的濃度。
用於純度分析之 HPLC 法 About 2-2 mg (N=5) of the test substance was weighed in a transparent test container and 300 μL of the solvent was added thereto. The test container was placed on a mechanical shaker and shaken at 37°C for 24 h of incubation time, filtered and the concentration of
於10 mL體積燒瓶中秤重大約10-10 mg之試驗物質,以及溶解於甲酸、乙腈及水之混合物中。使用100 mL體積燒瓶以該溶劑混合物將1 mL之該溶液稀釋至100 mL。然後使用Acquity CSH管柱將經稀釋之溶液注入Waters Acquity H-Class UPLC儀。Weigh approximately 10-10 mg of the test substance in a 10 mL volume flask and dissolve in a mixture of formic acid, acetonitrile and water. Dilute 1 mL of the solution to 100 mL with the solvent mixture using a 100 mL volume flask. Then inject the diluted solution into a Waters Acquity H-Class UPLC instrument using an Acquity CSH column.
活性物質之物理化學及生物醫藥特徵在活體內及活體外表現方面至關重要。理想狀況係,就口服固體劑型而言,水溶性、非吸濕、安定且容易加工之結晶化合物對於研發目的是較佳的。本文所揭露之化合物1之鹽及晶形及其鹽酸鹽的物理化學及調配相關性質可藉由下列方法進一步表示特徵:The physicochemical and biopharmaceutical properties of active substances are crucial in terms of in vivo and in vitro performance. Ideally, for oral solid dosage forms, crystalline compounds that are water-soluble, non-hygroscopic, stable and easy to process are preferred for development purposes. The physicochemical and formulation-related properties of the salts and crystalline forms of
晶癖:結晶多形材料可取決於用於最終結晶的方法及溶劑而以一些形狀或形式(有時稱為「晶癖」)存在。其範圍可從具有長形、針狀晶體及扁平板狀形式之高角度晶體至更為球形之晶癖。因粒子-粒子機械及物理相互作用或內聚力之故,其形狀可影響例如從容器/加料漏斗等排出期間之散裝粉末的流動性。藥物粒子之形狀可例如以偏光顯微術(PLM)表示特徵。Crystal habit: Crystalline polymorphic materials can exist in a number of shapes or forms (sometimes referred to as "crystal habits") depending on the method and solvent used for the final crystallization. This can range from high angle crystals with elongated, needle-like crystals and flat plate-like forms to more spherical crystal habits. The shape can affect the flowability of bulk powders, e.g., during discharge from a container/addition funnel, etc., due to particle-particle mechanical and physical interactions or cohesive forces. The shape of drug particles can be characterized, e.g., by polarizing light microscopy (PLM).
粒度分布:從藥物調配方面來看,活性醫藥成分之窄範圍及單峰粒度分布是有利的。粒度分布之測量可例如藉由雷射繞射法及偏光顯微術進行。Particle size distribution: From the perspective of drug formulation, a narrow and monomodal particle size distribution of the active pharmaceutical ingredient is advantageous. Particle size distribution can be measured, for example, by laser diffraction and polarizing microscopy.
該固體形式之比表面積可藉由氣體吸收(例如BET)或透氣性方法測定。The specific surface area of the solid form can be determined by gas absorption (such as BET) or gas permeability method.
溶解:溶解度對於選擇會影響溶解速率之鹽形式或特定結晶或多形形式而言相當重要,其為最關鍵的參數。溶解為物質形成溶液的程序。溶解試驗測量由劑型諸如錠劑、膠囊、油膏等形成溶液之程度及速率。藥物之溶解對其生物利用率及治療有效性相當重要。溶解及藥物釋出係可互換使用之術語。多形體之間的溶解度及溶解速率之差異對於醫藥之口服生物利用率(溶解及從GI道吸收)可具有顯著影響。Dissolution: Solubility is important in selecting a salt form or a specific crystalline or polymorphic form which will affect the dissolution rate and is the most critical parameter. Dissolution is the process by which a substance forms a solution. Dissolution tests measure the extent and rate of solution formation from dosage forms such as tablets, capsules, ointments, etc. The dissolution of a drug is important for its bioavailability and therapeutic effectiveness. Dissolution and drug release are terms used interchangeably. Differences in solubility and dissolution rate between polymorphs can have a significant effect on the oral bioavailability (dissolution and absorption from the GI tract) of a drug.
流動性:雖然錠劑及膠囊這兩種最常見的固體劑型具有其獨特的要求,但其間有相似之處。彼等均需要正確重量之材料流入特定體積。良好流動性質為成功製造錠劑以及粉末填充之硬明膠膠囊或小包裝藥二者的必備條件。歐洲藥典(European Pharmacopoeia)(Ph. Eur.)含有根據粉末如何垂直流出漏斗之關於粉末的流動性之試驗。有數種不同方法可用於測定粉末之流動性質,以及有許多文獻實例說明試驗方法與調配物之製造性質之間的相關性。Flowability: Although the two most common solid dosage forms, tablets and capsules, have their own unique requirements, there are similarities between them. They both require the correct weight of material to flow into a specific volume. Good flow properties are essential for the successful manufacture of both tablets and powder-filled hard gelatin capsules or sachets. The European Pharmacopoeia (Ph. Eur.) contains a test for the flowability of powders based on how the powder flows vertically out of a funnel. There are several different methods that can be used to determine the flow properties of powders, and there are many examples in the literature that illustrate the correlation between the test methods and the manufacturing properties of the formulation.
體密度為醫藥產品及方法研發及固體劑型製造之基本參數。其係用於測定可裝入某一空間諸如在錠劑壓機或膠囊填充器上之摻合機或加料漏斗的粉末之量。亦可用以測定可裝入具有特定體積之膠囊的粉末量。Bulk density is a fundamental parameter in pharmaceutical product and process development and solid dosage form manufacturing. It is used to determine the amount of powder that can be packed into a certain space, such as a blender or feed hopper on a tablet press or capsule filler. It can also be used to determine the amount of powder that can be packed into a capsule of a specific volume.
振實體密度或簡稱振實(tapped/tap)密度為在經良好界定之外部施加力的影響下所獲致之粉末(或粉末之摻合物)之最大堆積密度。最小堆積體積因而視許多因素,包含粒度分布、真密度、粒子形狀及因包含水分之表面力所致的內聚性而獲致。因此,材料之振實密度可用以預測其流動性質及其壓縮性。The tapped density or simply tapped density is the maximum bulk density of a powder (or blend of powders) that is achieved under the influence of a well-defined externally applied force. The minimum bulk volume is therefore dependent on many factors, including particle size distribution, true density, particle shape and cohesion due to surface forces including water. Therefore, the tapped density of a material can be used to predict its flow properties and its compressibility.
術語「與MCHR1活性相關之疾病或病況」係指肥胖症、肥胖症相關之共病病況及併發症、糖尿病、代謝失調、冠狀動脈疾病、腦血管疾病、周邊動脈疾病、高血壓、內分泌失調、精神疾患、人格障礙、飲食障礙、睡-醒周期障礙、物質濫用及成癮障礙、慢性肝臟及腎臟疾病、腸胃道疾病、肌肉骨骼系統之慢性病況、骨質疏鬆症、癌症。The term "diseases or conditions associated with MCHR1 activity" refers to obesity, obesity-related comorbid conditions and complications, diabetes, metabolic disorders, coronary artery disease, cerebrovascular disease, peripheral arterial disease, hypertension, endocrine disorders, mental illness, personality disorders, eating disorders, sleep-wake cycle disorders, substance abuse and addiction disorders, chronic liver and kidney diseases, gastrointestinal diseases, chronic conditions of the musculoskeletal system, osteoporosis, and cancer.
本文係參考由本案發明人所提交之標題為「
用於治療普威二氏症候群 MCHR1 拮抗劑」的平行專利申請案領域,其中,揭露使用根據WO 2016/166684 A1之式(I)的化合物,諸如呈游離形式、或呈醫藥上可接受之鹽形式例如其鹽酸鹽的化合物1治療普威二氏症候群之方法。
This article refers to the field of a parallel patent application entitled “ MCHR1 antagonist for treating Prader-Willi syndrome ” filed by the inventor of the present case, which discloses a method for treating Prader-Willi syndrome using a compound of formula (I) according to WO 2016/166684 A1, such as
術語「醫藥組成物」係指化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A與其他化學組分諸如醫藥上可接受之賦形劑例如稀釋劑或載劑的混合物。醫藥組成物促進化合物投服至個體。The term "pharmaceutical composition" refers to Compound 1 Form A,
術語「賦形劑」定義為促進化合物併入細胞或組織之化學化合物。The term "excipient" is defined as a chemical compound that enhances the incorporation of a compound into cells or tissues.
本發明之醫藥組成物可以許多方式調配,例如,呈錠劑、膠囊、粉末、顆粒、懸浮液、乳液、溶液、糖漿、氣溶膠(具有固態或液態載體)、軟或硬明膠膠囊、栓劑、呈滅菌形式之注射劑。較佳的,醫藥組成物係調配成錠劑或膠囊。The pharmaceutical composition of the present invention can be formulated in many ways, for example, in the form of tablets, capsules, powders, granules, suspensions, emulsions, solutions, syrups, aerosols (with solid or liquid carriers), soft or hard gelatin capsules, suppositories, and injections in sterile form. Preferably, the pharmaceutical composition is formulated in the form of tablets or capsules.
醫藥組成物可呈含有預定量之活性成分的單一劑型。該劑型可含有治療有效量之化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A或給定百分比之治療有效量,以使此等用於重複投服之單一劑型可在給定期間投服以達到所希望的治療有效劑量。較佳之單一劑型為含有每日劑量或子劑量或如上述之給定百分比之活性成分者。此外,此等醫藥組成物可藉由本領域中已知之方法製造。The pharmaceutical composition may be in a single dosage form containing a predetermined amount of active ingredient. The dosage form may contain a therapeutically effective amount of
術語「治療有效量」係指相較於未接受此量之個體,導致治療、治癒、預防、緩和或改善疾病、病理狀況、副作用、疾病之一或多種症狀(諸如過食症)以維持或減輕體重或減少食物攝取量,或者抑制或延緩疾病、疾病之病理狀況或一或多種症狀(諸如過食症)之進展程度的活性成分之量。該術語亦包含改善正常生理功能所需之有效量。於治療應用中,化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A可以治療有效量以未經調配之藥物物質投服,或活性成分可調配成藥物。此化合物之精確的治療有效量取決於數個因素,包含但不排除個體(病患)之年齡及體重、欲治療之疾病的類型及嚴重性、醫藥組成物/藥物之種類及投服方式。The term "therapeutically effective amount" refers to the amount of active ingredient that results in the treatment, cure, prevention, alleviation or improvement of a disease, pathological condition, side effect, one or more symptoms of a disease (such as overeating) to maintain or reduce body weight or reduce food intake, or inhibit or delay the progression of a disease, pathological condition of a disease, or one or more symptoms (such as overeating) compared to an individual who has not received such amount. The term also includes an effective amount required to improve normal physiological function. In therapeutic applications,
術語「每日劑量」意指每日投服之游離鹼的量。於投服醫藥上可接受之鹽的情況下,每日劑量亦以游離鹼之當量表示。The term "daily dose" means the amount of free base administered daily. In the case of administration of pharmaceutically acceptable salts, the daily dose is also expressed in free base equivalents.
於一實施態樣中,化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A之治療有效量為每日劑量為至少約2.5 mg。In one embodiment, the therapeutically effective amount of
於另一實施態樣中,化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A之治療有效量為每日劑量為約2.5 mg至約22.5 mg。In another embodiment, the therapeutically effective amount of
於一較佳實施態樣中,化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A之治療有效量之治療有效量為每日劑量為約2.5 mg至約7.5 mg。In a preferred embodiment, the therapeutically effective amount of
於一特佳實施態樣中,化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A之治療有效量為每日劑量為約2.5 mg、約5 mg或約7.5 mg。In a particularly preferred embodiment, the therapeutically effective amount of
術語「有效量」係指於所投服之個體中,足以引出例如研究員或臨床醫生正在尋求之組織、系統、動物(包含人類)的生物或藥物反應之藥物或活性成分的量。The term "effective amount" refers to the amount of a drug or active ingredient sufficient to elicit the biological or medicinal response in a tissue, system, animal (including human) to which the drug is administered, for example.
術語「個體」係指需要下文定義之方法1.1至1.7中任一項之病患。The term "subject" refers to a patient requiring any of methods 1.1 to 1.7 as defined below.
化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A可以任何適當途徑,例如藉由口服、直腸、經皮、皮下、局部、靜脈內、肌內、或鼻內途徑投服。較佳之投服途徑為口服。
於一系列另外的具體或者替代實施態樣中,本發明提供:
1.1. 一種用於治療有需要之個體中MCHR1活性相關之疾病或病況的方法,其包含對該個體投服治療有效量之如本文所述的化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A。
1.2. 一種用於治療有需要之個體中普威二氏症候群之方法,其包含對該個體投服治療有效量之如本文所述的化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A。
1.3. 一種用於改善、緩和或延遲有需要之個體中PWS之一或多種症狀進展的方法,其包含對該個體投服治療有效量之如本文所述的化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A。
1.4. 一種用於維持有需要之個體中罹患PWS之病患的體重之方法,其包含對該個體投服治療有效量之如本文所述的化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A。
1.5. 一種用於減輕有需要之個體中罹患PWS之病患的體重之方法,其包含對該個體投服治療有效量之如本文所述的化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A。
1.6. 一種用於減少有需要之個體中罹患PWS之病患的食物攝取量之方法,其包含對該個體投服治療有效量之如本文所述的化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A。
1.6. 一種用於治療有需要之個體中罹患PWS之病患的過食症之方法,其包含對該個體投服治療有效量之如本文所述的化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A。
1.7. 一種如上述之方法,其中化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A係每日投服一次。
2. 一種用於方法1.1至1.7中任一項之醫藥組成物,其包含如本文所述之化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A與一或多種醫藥上可接受之賦形劑。
4. 如本文所述之化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A,其用於方法1.1至1.7中任一項。
5. 如本文所述之化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A,其用於製備用於方法1.1至1.7中任一項之藥物。
6. 如本文所述之化合物1形式A、化合物1形式D、化合物1鹽酸鹽、呈晶形之化合物1鹽酸鹽、或化合物1鹽酸鹽形式A之用途,用於方法1.1至1.7中任一項。
In a series of additional specific or alternative embodiments, the present invention provides:
1.1. A method for treating a disease or condition associated with MCHR1 activity in an individual in need thereof, comprising administering to the individual a therapeutically effective amount of
特別是,如本文所述之化合物1鹽酸鹽形式A可用於治療罹患PWS之病患的過食症。In particular,
本發明之其他細節呈現於下列實例,本發明之保護範圍在任何方面限制均不局限於所述之實例。除非於個別實例中明確表示,否則下列實例之起始材料係根據WO 2016/166684實施例20(a)製備-化合物1游離鹼,或根據20(b)製備-化合物1順丁烯二酸鹽。
參考例
Other details of the present invention are presented in the following examples, and the scope of protection of the present invention is not limited to the examples described in any aspect. Unless explicitly stated in individual examples, the starting materials of the following examples are prepared according to Example 20 (a) of WO 2016/166684 -
參考例1
來自乙醇之化合物1順丁烯二酸鹽溶劑合物
向0.47 g(1.015 mmol)之化合物1(WO 2016/166684實施例20/a)於二氯甲烷與甲醇之10:1混合物的溶液中,添加0.13 g(1.117 mmol)之順丁烯二酸,以及濃縮該混合物。以乙醇滴定殘留物,以及在攪拌1 h之後過濾固態產物,以乙醇洗滌、以及乾燥以獲得0.57 g(96%)之標題化合物。產物之XRPD圖係顯示於圖1。TGA:3.9%(圖10)。
Reference Example 1
參考例2
來自乙醇之化合物1順丁烯二酸鹽溶劑合物
將99.11 mg化合物1順丁烯二酸鹽溶解於5 ml乙醇(夾套溫度70℃),過濾且將濾液冷卻至25℃,攪動30 min,過濾且於室溫下靜置至乾達4天。產物之XRPD圖係顯示於圖2。TG:5.1%(圖11)
Reference Example 2
參考例3
來自二氯甲烷/乙醇之化合物1順丁烯二酸鹽溶劑合物
將0.231 kg 4-[(5-氯吡啶-2-基)甲氧基]-l-{lH,2H,3H,4H,5H-[l,4]二氮呯并[l,7-a]吲哚-9-基}-l,2-二氫吡啶-2-酮(WO 2016/166684中之實施例4)溶解於20 l乙腈,以及添加0.3 kg K
2CO
3及520 ml 2-碘丙烷且在回流攪動10 h,以及藉由蒸發溶劑(100 mbar,40-45℃)單離產物。將粗製產物溶解於1.1 L二氯甲烷且以3×1 l水洗滌,以及藉由蒸發溶劑(100 mbar,40-45℃)單離粗製鹼。將固體溶解於1.5 l二氯甲烷且於其中添加65 g順丁烯二酸於3.6 l乙醇中之溶液。懸浮液係藉由蒸發3.1 l溶劑而濃縮,添加2 l乙醇以及使另外1.5 l蒸發,所得之懸浮液係於20-25℃攪動一小時,冷卻至10-12℃,攪動一小時,過濾,以2×0.5 l乙醇洗滌以及於75-80℃乾燥7小時以獲得0.197 kg白色固體。產物之XRPD圖係顯示於圖3。TGA:4.1% (圖12)。
Reference Example 3
參考例4
來自甲醇之化合物1順丁烯二酸鹽溶劑合物
將40 mg之化合物1之順丁烯二酸鹽懸浮於1 ml甲醇中,攪動一週,過濾及在環境條件下乾燥。產物之XRPD圖係顯示於圖4。TGA:5.5%(圖13)。
Reference Example 4
參考例5
來自乙醇之化合物1順丁烯二酸鹽溶劑合物
將40 mg之化合物1之順丁烯二酸鹽懸浮於1 ml乙醇中,攪動一週,過濾及藉由XRPD分析。產物之XRPD圖係顯示於圖5。TGA:4.7%(圖14)
Reference Example 5
參考例6
來自乙醇之化合物1順丁烯二酸鹽溶劑合物
向0.47 g(1.015 mmol)之化合物1於5 ml之二氯甲烷與甲醇之10:1混合物的溶液中,添加0.13 g順丁烯二酸於3.5 ml相同溶劑中之溶液,以及藉由Rotavapor(500-350 mbar,40℃)蒸發混合物。於固態殘留物中添加1.9 ml乙醇,攪動一小時,過濾且於室溫下靜置至乾。產物之XRPD圖係顯示於圖6。TGA:1,9%(圖15)
Reference Example 6
參考例7
來自甲醇之化合物1順丁烯二酸鹽溶劑合物
將50 mg之化合物1之順丁烯二酸鹽溶解於1 ml甲醇中,以及於室溫蒸發溶劑。固體之XRPD圖係顯示於圖7。TGA:4.3%(圖16)。
Reference Example 7
Solution of maleic acid salt of
參考例8
來自甲醇之化合物1順丁烯二酸鹽溶劑合物
將101 mg之化合物1之順丁烯二酸鹽懸浮於2.5 ml甲醇中,攪動一週,過濾及藉由XRPD分析。產物之XRPD圖係顯示於圖8。樣本係於40℃乾燥一夜。TGA:2.7%(圖17)。
Reference Example 8
參考例9
來自DMSO之化合物1順丁烯二酸鹽溶劑合物
將272 mg之化合物1之順丁烯二酸鹽懸浮於0.75 ml DMSO中且於室溫攪動一週。過濾固體且藉由XRPD分析。產物之XRPD圖係顯示於圖9。
Reference Example 9
參考例10
將0.6 g化合物1溶解於5 ml二氯甲烷、甲醇與氨之95:5:0.1混合物。於Rotavapor中蒸發溶劑(40℃ 500 mbar)以獲得0.6 g米白色粉末。產率:100%。產物之XRPD係顯示於圖40。
實施例
Reference Example 10
0.6 g of
實施例1
向30 mg化合物1之游離鹼於1.2 ml丙酮中之溶液逐滴添加7.5 µl 37%鹽酸,攪動3 h,過濾以及於40℃/真空乾燥。產率:N/A。產物之XRPD圖係根據圖18,以及藉由TGA測量之含水量為0.6%(至200℃) 。
Example 1
To a solution of 30 mg of the free base of
實施例2
向3 g化合物1之游離鹼於36 ml二氯甲烷中之溶液添加0.6 ml cc.鹽酸於36丙酮中之溶液。使所得之懸浮液冷卻至0℃且攪動3小時。過濾固體,以丙酮洗滌以及於60℃乾燥以獲得3.10 g化合物1鹽酸鹽。產率:96%。產物之XRPD圖、FT-IR及FT-拉曼光譜、DSC及TGA曲線係顯示於圖18至22。
Example 2
To a solution of 3 g of the free base of
實施例3
將5.23 g粗製化合物1游離鹼溶解於30 ml二氯甲烷、15 ml乙醇及15 ml甲苯之混合物中以及藉由蒸發濃縮。產物係藉由管柱層析術使用Kieselgel 60(0.040-0.063 mm)作為吸附劑以及二氯甲烷、甲醇及cc. NH
3溶液之95:5:0.1混合物作為溶析液來純化。移除溶析液(Rotavapor)以及將產物再懸浮乙醇中、乾燥、再懸浮於二乙醚中以及過濾以獲得1.24 g白色晶體。產物之XRPD圖係顯示於圖41,證實其為化合物1形式B及化合物1形式A的混合物。
Example 3 5.23 g of
實施例4
將100 mg化合物1游離鹼,形式A及形式B之混合物懸浮於2 ml乙醇中,以及在室溫下攪動一週。過濾固體以及藉由XRPD識別為化合物1形式A。
Example 4
100 mg of a mixture of
實施例5
於回流下將96.76 mg化合物1溶解於11 ml乙醇,冷卻以及攪動大約3天以獲得識別為化合物1游離鹼形式A之白色沉澱物。產物之XRPD圖係根據圖23。
Example 5
96.76 mg of
實施例6
將83.5 mg化合物1游離鹼溶解於15 ml乙腈以及於開放式小瓶中攪拌兩天,過濾固體以獲得識別為化合物1游離鹼形式A之白色至米白色沉澱物。產物之XRPD圖係根據圖23。
Example 6
83.5 mg of
實施例7
將1.17 g化合物1游離鹼溶解於13.2 ml二氯甲烷以及將2 ml之該溶液添加至2 ml四氫呋喃以及攪動一夜以獲得識別為化合物1游離鹼形式A之白色沉澱物。產物之XRPD圖係根據圖23。
Example 7
1.17 g of
實施例8
將1.17 g化合物1游離鹼溶解於13.2 ml二氯甲烷以及將2 ml之該溶液添加至2 ml甲基三級丁基醚以獲得識別為化合物1游離鹼形式B之白色沉澱物。產物之XRPD圖係根據圖28。
Example 8
1.17 g of
實施例9
將51.20 mg之化合物1順丁烯二酸鹽懸浮於1.5 ml吡啶以及攪動一週。過濾固體以及於真空中以40℃乾燥以獲得化合物1游離鹼形式C。樣本之XRPD圖係顯示於圖36,TGA:10.3%(圖34)。NMR:化合物1,以0.4莫耳吡啶及0.15莫耳順丁烯二酸確認。於DSC上偵測形式A之熔融(圖33)。
Example 9
51.20 mg of
實施例10
將131.5 g化合物1游離鹼溶解於18.5 ml二氯甲烷以及將1.2 ml之該溶液添加至1 ml摻有17 µl cc. HCl之正己烷。過濾固體以及於40℃乾燥。樣本之XRPD圖係根據圖35,確認為化合物1形式D。TGA:4.1%(215℃)。
Example 10
131.5 g of
實施例11
於回流下將1 g化合物1游離鹼於50 ml四氫呋喃之溶液添加至150 ml水,攪動一小時,以水過濾洗滌。樣本之XRPD圖係根據圖35。
醫藥組成物之製備 Example 11 A solution of 1 g of
下列調配實例說明本發明之個別醫藥組成物。然而本發明不限於下列醫藥組成物。
[圖1]圖示說明參考例1中所獲得之化合物1順丁烯二酸鹽的X射線繞射圖。
[圖2]圖示說明參考例2中所獲得之化合物1順丁烯二酸鹽的X射線繞射圖。
[圖3]圖示說明參考例3中所獲得之化合物1順丁烯二酸鹽的X射線繞射圖。
[圖4]圖示說明參考例4中所獲得之化合物1順丁烯二酸鹽的X射線繞射圖。
[圖5]圖示說明參考例5中所獲得之化合物1順丁烯二酸鹽的X射線繞射圖。
[圖6]圖示說明參考例6中所獲得之化合物1順丁烯二酸鹽的X射線繞射圖。
[圖7]圖示說明參考例7中所獲得之化合物1順丁烯二酸鹽的X射線繞射圖。
[圖8]圖示說明參考例8中所獲得之化合物1順丁烯二酸鹽的X射線繞射圖。
[圖9]圖示說明參考例9中所獲得之化合物1順丁烯二酸鹽的X射線繞射圖。
[圖10]圖示說明參考例1中所獲得之化合物1順丁烯二酸鹽的TGA溫度記錄圖。
[圖11]圖示說明參考例2中所獲得之化合物1順丁烯二酸鹽的TGA溫度記錄圖。
[圖12]圖示說明參考例3中所獲得之化合物1順丁烯二酸鹽的TGA溫度記錄圖。
[圖13]圖示說明參考例4中所獲得之化合物1順丁烯二酸鹽的TGA溫度記錄圖。
[圖14]圖示說明參考例5中所獲得之化合物1順丁烯二酸鹽的TGA溫度記錄圖。
[圖15]圖示說明參考例6中所獲得之化合物1順丁烯二酸鹽的TGA溫度記錄圖。
[圖16]圖示說明參考例7中所獲得之化合物1順丁烯二酸鹽的TGA溫度記錄圖。
[圖17]圖示說明參考例8中所獲得之化合物1順丁烯二酸鹽的TGA溫度記錄圖。
[圖18]圖示說明化合物1鹽酸鹽形式A之X射線繞射圖。
[圖19]圖示說明化合物1鹽酸鹽形式A之紅外線光譜。
[圖20]圖示說明化合物1鹽酸鹽形式A之拉曼光譜。
[圖21]圖示說明化合物1鹽酸鹽形式A之DSC記錄曲線。
[圖22]圖示說明化合物1鹽酸鹽形式A之TGA溫度記錄圖。
[圖23]圖示說明化合物1游離鹼形式A之X射線繞射圖。
[圖24]圖示說明化合物1游離鹼形式A之紅外線光譜。
[圖25]圖示說明化合物1游離鹼形式A之拉曼光譜。
[圖26]圖示說明化合物1游離鹼形式A之DSC記錄曲線。
[圖27]圖示說明化合物1游離鹼形式A之TGA溫度記錄圖。
[圖28]圖示說明化合物1游離鹼形式B之X射線繞射圖。
[圖29]圖示說明化合物1游離鹼形式B之紅外線光譜。
[圖30]圖示說明化合物1游離鹼形式B之拉曼光譜。
[圖31]圖示說明化合物1游離鹼形式B之DSC記錄曲線。
[圖32]圖示說明化合物1游離鹼形式C之X射線繞射圖。
[圖33]圖示說明化合物1游離鹼形式C之DSC記錄曲線。
[圖34]圖示說明化合物1游離鹼形式C之TGA溫度記錄圖。
[圖35]圖示說明化合物1游離鹼形式D之X射線繞射圖。
[圖36]圖示說明化合物1游離鹼形式D之紅外線光譜。
[圖37]圖示說明化合物1游離鹼形式D之拉曼光譜。
[圖38]圖示說明化合物1游離鹼形式D之DSC記錄曲線。
[圖39]圖示說明化合物1游離鹼形式D之TGA溫度記錄圖。
[圖40]圖示說明參考例10中所獲得之化合物1游離鹼的X射線繞射圖。
[圖41]圖示說明實施例3中所獲得之化合物1游離鹼的X射線繞射圖。
[Figure 1] is a diagram illustrating an X-ray torsion pattern of the maleic acid salt of
Claims (38)
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HUP2200221 HUP2200221A1 (en) | 2022-06-17 | 2022-06-17 | Crystalline forms of 4-[(5-chloropyridin-2-yl)methoxy]-1-[3-(propan-2-yl)-1h,2h,3h,4h,5h- [1,4]diazepino[1,7-a]indol-9-yl]-1,2-dihydropyridin-2-one and salts thereof, method of preparation, and uses thereof |
HUP2200221 | 2022-06-17 |
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